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Rapid CommunicationShort Communication

In Vitro Interaction of Codeine and Diclofenac

Susanne Ammon, Oliver von Richter, Ute Hofmann, Klaus-Peter Thon, Michel Eichelbaum and Gerd Mikus
Drug Metabolism and Disposition October 2000, 28 (10) 1149-1152;
Susanne Ammon
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Oliver von Richter
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Ute Hofmann
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Klaus-Peter Thon
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Michel Eichelbaum
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Gerd Mikus
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Abstract

There is very limited knowledge about possible pharmacokinetic interactions between opioid analgesics and nonsteroidal antiinflammatory drugs (NSAIDs), which are commonly used in combination for the treatment of chronic pain. The major metabolic pathway of the weak opioid codeine is glucuronidation to codeine-6-glucuronide. Therefore we investigated the influence of the NSAID diclofenac on the formation of codeine-6-glucuronide in vitro, using human liver tissue homogenate. The formation of codeine-6-glucuronide exhibited single enzyme Michaelis-Menten kinetics with an averageVmax of 93.6 ± 35.3 pmol/mg/min. A noncompetitive inhibition of codeine-6-glucuronidation by diclofenac was observed with an average Ki of 7.9 μM. These in vitro findings suggest that a pharmacokinetic interaction occurs in vivo, which has to be confirmed by an interaction study in human subjects. It can be speculated that in case of inhibition of glucuronidation, the amount of codeine available for other pathways especially O-demethylation to morphine is increased, resulting in higher morphine serum levels and therefore higher analgesic efficacy.

Footnotes

  • Send reprint requests to: Susanne Ammon, M.D., Institute for Pharmacology and Toxicology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. E-mail:susanne.ammon{at}medizin.uni-magdeburg.de

  • The study was fully supported by the Robert Bosch Foundation, Stuttgart, Germany.

  • Abbreviations used are::
    NSAIDs
    nonsteroidal anti-inflammatory drugs
    UGT
    UDP-glucuronosyltransferase
    UDPGA
    uridine 5′-diphosphoglucuronic acid
    CV
    coefficient of variation
    Cli
    intrinsic clearance
    • Received April 25, 2000.
    • Accepted July 19, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (10)
Drug Metabolism and Disposition
Vol. 28, Issue 10
1 Oct 2000
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Rapid CommunicationShort Communication

In Vitro Interaction of Codeine and Diclofenac

Susanne Ammon, Oliver von Richter, Ute Hofmann, Klaus-Peter Thon, Michel Eichelbaum and Gerd Mikus
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1149-1152;

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Rapid CommunicationShort Communication

In Vitro Interaction of Codeine and Diclofenac

Susanne Ammon, Oliver von Richter, Ute Hofmann, Klaus-Peter Thon, Michel Eichelbaum and Gerd Mikus
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1149-1152;
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